The potential of overdiagnosis and overtreatment of small renal tumors remains a significant concern. It has been estimated that more than 5,000 people per year in the United States alone are having benign renal masses surgically resected. However, there is no ideal method that is clinically applicable or available so far. Limitations stll exist in currently methods for RCC diagnosis, including the invasive renal mass biopsy, highly variable contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI) and 2-deoxy-2- [18F]fluoro-D-glucose (FDG) positron emission tomography (PET). This proposal aims to develop highly specific PET radiotracers, which are able to provide characteristic biological process information for malignant renal cell carcinoma (RCC) diagnosis. We will develop low-molecular-weight (LMW) agents targeting carbonic anhydrase IX (CA IX), proved to be specifically expressed on clear cell renal cell carcinomas (ccRCCs). We will start with a low potency but very specific peptide ligand. After optimizing its potency and bio-stability we anticipate imaging of ccRCC via LMW [18F] PET tracers, with high binding affinity and specificity, faster normal tissue clearance and less organ uptake. These tracers will also help a broad spectrum of biomedical applications related with tumor hypoxia detection.